Cancer is a worldwide epidemic claiming over 7.6 million lives per year and is the leading cause of death in developed countries (International Agency for Research on Cancer. Cancer Mondial 2010. Lyon, France: World Health Organization; Jemal, A., et al. Global cancer statistics. CA Cancer J Clin 61, 69-90 (2011)). In the US alone, current statistics estimate that over the course of a lifetime 1 in 2 men and 1 in 3 women will develop some form of cancer (American Cancer Society. Cancer Facts & Figures 2010. Atlanta, Ga.: American Cancer Society (2010); International Agency for Research on Cancer. Cancer Mondial 2010. Lyon, France: World Health Organization (2010)). While cancer can be characterized by persistent cell proliferation, inhibition of apoptosis, and altered cell migratory behavior, cancer is, at its core, a disease of dysregulated signal transduction (Hanahan, D. and Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000); Dhillon, A. S., et al. MAP kinase signaling pathways in cancer. Oncogene 26, 3279-3290 (2007)). Targeting key signaling cascades that regulate these processes will lead to the development of efficacious therapeutics.
Mitogen activated protein kinase (MAPK) cascades are evolutionarily conserved three-tier phosphorylation relays. A MAPK kinase kinase (MAPKKK) phosphorylates and activates downstream target MAPK kinase (MAPKK), which in turn phosphorylates and activates downstream target MAPK (Dhillon, A. S., et al. MAP kinase signaling pathways in cancer. Oncogene 26, 3279-3290 (2007)). The extracellular signal-regulated kinase (ERK) MAPK pathway is probably the most well-known MAPK cascade (Kolch, W., et al. The role of RAF kinases in malignant transformation. Expert Rev Mol Med 4, 1-18 (2002)). In this pathway, the MAPKKK are C-RAF-1, A-RAF, and B-RAF with MEK1 and MEK2 acting as MAPKK and ERK1 and ERK2 denoted as MAPK. This cascade is initiated by activation of RAS, the first identified human oncogene (Tabin, C. J., et al. Mechanism of activation of a human oncogene. Nature 300, 143-149 (1982)). As this pathway is capable of regulating proliferation, differentiation, migration, and survival, it is not surprising that more than one-third of all human cancers are characterized by pathologic activation of this pathway, most often as a result of constitutive activation of core kinases (FIG. 1A) (Kolch, W., et al. The role of RAF kinases in malignant transformation. Expert Rev Mol Med 4, 1-18 (2002); Hoshino, R., et al. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18, 813-22 (1999); Schubbert, S., et al. Hyperactive RAS in developmental disorders and cancer. Nature Rev. Cancer 7, 295-308 (2007); Dhillon, A. S., et al. MAP kinase signaling pathways in cancer. Oncogene 26, 3279-3290 (2007); Reddy, K. B., et al. Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev 22, 395-403 (2003)). Targeting this pathway may prove efficacious in treating cancer (FIG. 1B).